3/19/2015
PARTICIPANT HANDOUT
GCP Refresher and
GCP/GCDMP Trends
in the CTN
Presented by:
Denise King, MS, RD, CCRA &
Lauren Yesko, BS
CTN WEB SEMINAR SERIES:
A FORUM TO EXCHANGE RESEARCH KNOWLEDGE
Produced by: CTN Training
This training has been funded in whole or in part with federal funds from the National Institute on Drug Abuse, National
Institutes of Health, Department of Health and Human Services, under Contract No.HHSN271201000024C
Learning Objectives
• Review principles and regulatory requirements for
Good Clinical Practice (GCP).
• Discuss staff roles and responsibilities, protocol
compliance, and other criteria for conducting quality
trials.
• Examine best practices, examples of GCP noncompliance, and corrective actions for protocol or
procedural deviations.
• Identify significant GCP and Good Clinical Data
Management Practice (GCDMP) trends in the CTN,
such as, informed consent, safety, documentation, drug
management, and data management.
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GOOD CLINICAL PRACTICE
FOR RESEARCH
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What is GCP?
• Good Clinical Practices: An international
ethical and scientific quality standard for
the:
 Design
 Conduct, performance, monitoring
 Recording, auditing and
 Analysis and reporting of…Research
Studies involving Human Subjects
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What is GCDMP?
• Good clinical data management
practice (GCDMP)
• The current industry standards
for clinical data management that
consist of best business practice
and acceptable regulatory standards
• In all phases of clinical trials, clinical and
laboratory information must be collected and
converted to digital form for analysis and
reporting purposes
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What are Research Studies
involving Human Subjects?
• Many types of human research—
 Clinical trials for medical products
 Laboratory studies on tissue samples
 Epidemiological research studies
 Behavioral research studies
 Marketing research studies
• All types benefit from use of GCP
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Where GCP is applied?
• Private industry, NIH, CDC, government,
research institutions, private practice
• Internationally adopted standards
• Formalized by regulations that vary in only
minor ways between countries
• Expected to be used universally
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Why GCP?
• Assurance to public
• Protection of rights, safety and well-being
of trial subjects
• Credible data based on scientific quality
standards
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Entities involved in human
research protection
Federal:
HHS (OHRP, FDA,
NIH)
Laws (CFR)
Human Subject
Protection
Clinical Trial:
Implementation of GCPs
International:
ICH (including FDA)
Institutional:
IRB
Policies /
Instructions
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ICH GCP Highlights—1
• Ethical principles paramount
• Risk-benefit assessment expected
• Individual subject rights & safety to
prevail over other interests
• Scientifically sound & detailed protocol
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ICH GCP Highlights—2
• IRB/Ethical committee approval
• Medical care by qualified physician
• All staff qualified for duties
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ICH GCP Highlights—3
• Informed consent for each subject
• Subject confidentiality protected
• All data recorded, handled & stored to
allow accurate reporting, interpretation
and verification
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ICH GCP Highlights—4
• Investigational products (IP) prepared in
accordance with GMP
• IP maintained according to approved protocol and
study Operations Manual
• Site level systems with procedures implemented
to assure quality of all aspects of trial
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Adoption of GCP Principles
• Governments and government agencies
(FDA, Health Canada, EU, etc.)
• Industry, e.g., Pharmaceutical Research
and Manufacturers of America (PhRMA)
and individual manufacturers
• Contract Research Organizations (CROs)
• Professional societies (clinical,
regulatory, medical)
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How do we “Do” GCP?
• Develop and use written, standard
procedures
 Investigators
 Sponsors
 Monitors and Auditors
 Data managers and IT staff
 Statisticians
 Regulatory authorities
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More on doing GCP—1
• Plan clinical trials carefully
 Provide adequate detailed instructions in
protocol and study manuals
 Incorporate guidance from regulators and
standards organizations
 Be precise with inclusion/exclusion criteria
 Clarify safety and efficacy endpoints
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More on doing GCP—2
• Select qualified investigators and staff
 Inform and train investigators
 Qualified, adequately trained, and committed
to quality research
 Communication with sponsor is essential
 Must follow protocol and SOPs
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More on doing GCP—3
• Documentation important
 Consent
 Study procedures
 Adverse event reporting
 Entering study data on time
 Annual IRB reviews and keeping
IRB up to date on changes
 Keeping staff and study subjects informed of
trial progress
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More on doing GCP—4
• Sponsor’s broad obligations






Quality assurance and quality control
Investigator’s Brochure
Manufacturing test article under GMP
Regulatory approvals to proceed
Monitoring, auditing study progress
Reports to investigators, regulators
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Quality Assurance (QA)
• Planned, systematic activities conducted to
ensure that a trial is performed and that trial
data are generated, documented, and
reported in compliance with
the protocol and with GCP
and all other applicable
regulatory requirement(s)
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Performing
Quality Assurance (QA)
• QA is the responsibility of every member of
the research team. The role of QA staff is to
support and assist members of the research
team in adhering to high quality standards.
• Internal and External QA
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Performing
Quality Assurance (QA)
• Monitoring verifies
– Rights and well-being of human participants are protected
– Reported trial data are accurate, complete, and verifiable
– The trial is conducted in compliance with the currently
approved protocol (including any amendments), as well as
with GCP and all other applicable regulatory
requirement(s)
• In general, on-site monitoring is
required before, during, and
after completion of a trial
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Performing
Quality Assurance (QA)
• All CTN studies undergo QA monitoring by the CCC
– Initiation, Interim, and Close-out visits
– File reports with the CTP, the local Node, NIDA and the
Lead Investigator as required
– Detailed Monitors’ responsibilities
• ICH GCP 5.18.4
• Good monitoring is not the enemy of good research;
it protects our participants and research
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More on doing GCP—5
• Essential documents maintained by
Investigator/Research Site
 Keeping documents together
 Preparing for sponsor visits
 Preparing for an FDA audit
(if applicable)
 Closing out a study
 Maintaining study documents after
conclusion of a study
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More on doing GCP—6
• Objectivity in research
 Recognizing and reducing bias
 Disclosing potential conflicts of interest
 Independent monitoring boards
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More on doing GCP—7
• Training of investigators and staff
 Study-specific procedures, tests
 Data recording methods
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GCP at Home and On the Road
• US requirements under Title 21 of the
Code of Federal Regulations (CFR):
312 (INDs for drugs and biologics)
812 (IDEs for medical devices)
50 (Protection of human subjects)
54 (Financial disclosures)
56 (IRBs)
Also 45 CFR 46 (the “Common Rule”)
• Everywhere, the ICH Guidelines for GCP
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GCP for Research—Conclusions
•
•
•
•
•
•
•
Broad applicability of GCP
Ethical standards paramount
Protections against unreasonable risks
Assures confidentiality of study participants
Quality in study design, data, and conclusions
Data useful for marketing approvals
Creates new and expanded treatment indications
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GCP Take-home Messages
•
•
•
•
•
•
Prepare & follow written procedures
Follow the protocol
Safety rules
Maintain confidentiality
Integrity of research data crucial
Know your Investigator responsibilities
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APPLYING GCP
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GCP Scenario 1
FOR AUDIENCE PARTICIPATION…
• The research trial required negative Hep A and B
prior to randomization. An investigator must sign
laboratory reports for each participant prior to
randomization.
• Protocol monitor noted that the lab results for 3
randomized participants had not been signed by
an investigator as required by the protocol.
• What next?
TYPE YOUR ANSWERS IN CHAT
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Note to File (NTF)
FILE NOTE
-----------------------------------------------Date: XX-XX-XXXX
From: Site Investigator, ABC
Research Site
To:
Study File
Re:
Procedural Departure
---------------------------------------------------------------------------------------------------------------------------
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GCP Scenario 2
FOR AUDIENCE PARTICIPATION…
• The research study’s MOP outlines procedures for
performing informed consent and documenting
the process.
• The protocol monitor discovered that there was
no documentation of the informed consent
process in 3 participant charts.
• What next?
TYPE YOUR ANSWERS IN CHAT
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FDA Warning Letters
http://www.accessdata.fda.gov/scripts/warningletters/
wlSearchResult.cfm?office=Center%20for%20Drug%
20Evaluation%20and%20Research
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Website for FDA Warning Letters
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FDA Warning Letters: Examples
• “You failed to ensure that the investigation was
conducted according to the investigational plan
[21 CFR 312.60]”
• “You failed to obtain informed consent in
accordance with the provisions of 21 CFR part 50
[21 CFR 312.60, 21 CFR 50.20]”
• “You failed to personally conduct or supervise
the clinical investigations [21 CFR 312.60]”
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Questions? Use the Chat
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GOOD CLINICAL DATA
MANAGEMENT PRACTICES
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Research Misconduct
• Definition
– Fraud: intentional deception
– Misconduct: intentional wrongdoing
– Falsification of data, either
through omission (failing
to reveal data) or
commission (altering or
fabricating data)
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Research Misconduct
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Research Misconduct
• Examples –
– Inadequate records:
• Creating source documents for missed assessments
• Throwing away source documents for assessments that
are supposed to be direct data entry
– Failure to report data (e.g., knowledge of an AE
that a coordinator assumes is unrelated)
– Backdating review of eligibility criteria
– Assuming result/answer
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EDC - Issues
• Sharing username and password access
– Compromises our ability to track data entry and
maintain 21 CFR part 11 compliance
– Each person using EDC
must be certified and
have their own ID
– Even applies to ePro
• Compromises integrity of “self-report” assessment
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EDC – Issues
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EDC - Issues
• Source Documents
– Initial point of collection for study data
– Note when direct data entry is required vs.
paper source docs
– Even a sticky note can
become a source document
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APPLYING GCDMP
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GCDMP Scenario 1
FOR AUDIENCE PARTICIPATION…
• Protocol monitor discovered missing source
documents for vitals and an EDC
questionnaire.
• Site Coordinator stated that these entries
were done via direct data entry.
• What next?
MULTIPLE CHOICE
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GCDMP Scenario 1
CHOOSE THE BEST ANSWER…
• Re-create the source document
• Indicate on progress note assessment was done
via direct data entry
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Paper First vs. Direct Data Entry
• Verify requirements for Source Documents or
Direct Data Entry for each assessment
– Do not create a paper source document if direct
data entry was used
• Verify data source (RA interview, Participant
self-report, Medical record abstraction)
• eCRF should match paper source document
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GCDMP Scenario 2
FOR AUDIENCE PARTICIPATION…
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GCDMP Scenario 2
• Data entry UDS results recording.
UDS results from
paper source:
UDS results in
EDC:
What next?
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GCDMP Scenario 2
CHOOSE THE BEST ANSWER…
• Assume missing was a negative result
– “Remember” it being negative
– Fix source document to match EDC
• Remove value in AdvantageEDC and submit
Missing Value Exception Request
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GCDMP Scenario 3
FOR AUDIENCE PARTICIPATION…
• In this research study, a Substance Use Assessment is direct data
entry into EDC.
• At the end of the day, an RA discovered that this assessment was
not recorded in EDC for a participant whose visit concluded early
morning.
INFORMATION ABOUT THE ASSESSMENT
• The assessment is an RA-administered interview.
• Based on other assessments conducted with this participant, the RA
knows that the participant did not use any substances.
• What next?
MULTIPLE CHOICE
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GCDMP Scenario 3
CHOOSE THE BEST RESPONSE…
• Complete assessment in EDC with data
indicating “no substance use”
• Submit Missing Form Exception Request
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GCDMP Scenario 4
Please note that
GCDMP Scenario 4 was
slightly modified after
the live webinar to
clarify the condition
presented.
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GCDMP Scenario 4
Protocol requirement:
Scenario: Participant presents with mild
acid reflux.
Is this AE reportable in EDC? YES or NO
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WRAPPING IT UP!
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Take Home Messages…
• Ongoing Training and Documentation
• Reference provided materials
– Study MOP
– AdvantageEDC User’s Guide/Data Management
Handbook
• Ask questions!
– Manuals may need to be updated to be clearer
• Bad data = useless study = waste of taxpayer
money
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References
•
•
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH). (2015). E6 Good Clinical
Practice. Retrieved from http://www.ich.org/products/guidelines.html.
U.S. Food and Drug Administration. (n.d.). FDA’s Electronic Reading Room –
Warning Letters. Retrieved from
http://www.accessdata.fda.gov/scripts/warningletters/wlSearchResult.cfm?office=Cen
ter%20for%20Drug%20Evaluation%20and%20Research.
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Questions / Comments
Alternatively, questions can be directed to the presenter(s)
by sending an email to [email protected].
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http://ctndisseminationlibrary.org
A copy of this presentation will be available electronically.
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THANK YOU FOR YOUR
PARTICIPATION
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